Ras is mutated in cancer more frequently than any other oncogene. Hence, Ras has been a focus for the development of rationally designed anti-cancer drugs, yet to date none have been successfully developed. In 1989, several groups showed that posttranslational modification of Ras proteins by farnesyl lipids is essential for Ras membrane association and transformation. Farnesyltransferase (FTase) was then purified and characterized and shortly thereafter, a second prenyltransferase, geranylgeranyltransferase type I (GGTase-I), that modifies Ras with a geranylgeranyl lipid was discovered. GGTase-I inhibitors (GGTIs) were studied and at least one such inhibitor, GGTI-2417, has been shown to inhibit the in vitro growth and survival of the MiaPaCa2 pancreatic cell line. But, these inhibitory effects were modest and no clinical trials with GGTIs have followed.
RalA and RalB are paralogs in the family of Ras monomeric G proteins that have approximately 85% amino acid identity, and play a role in the regulation of endocytosis, exocytosis, actin cytoskeletal dynamics, and transcription. Like Ras, Ral proteins have also been implicated in tumorigenesis and metastasis. Ral GTPases may be activated in a Ras-dependent manner, via several guanidine nucleotide exchange factors, including RalGDS. Activation of the Ral pathway has been shown to be a requirement for transformation of human cells (Rangarajan A, Hong S J, Gifford A, Weinberg R A. Species- and cell type-specific requirements for cellular transformation. Cancer Cell 2004; 6:171-83; Hamad N M, Elconin J H, Kamoub A E, et al. Distinct requirements for Ras oncogenesis in human versus mouse cells. Genes Dev 2002; 16:2045-57), and Ras-mediated transformation depends on activation of RalA (Lim K H, Baines A T, Fiordalisi J J, et al. Activation of RalA is critical for Ras-induced tumorigenesis of human cells. Cancer Cell 2005; 7:533-45). RalA and RalB also play a role in the transcriptional regulation of CD24, a metastasis-associated gene in bladder and other cancers (Smith S C, Oxford G, Wu Z, et al. The metastasis associated gene CD24 is regulated by Ral GTPase and is a mediator of cell proliferation and survival in human cancer. Cancer Res 2006; 66:1917-22).
Thus, Ral GTPases present a compelling therapeutic target for the prevention and treatment of solid tumors and the metastasis of these cancers, and there exists a need for effective methods of inhibiting Ral GTPases for the treatment and prevention of cancer.